Vaccination against infectious diseases remains an important and cost-effective goal for public health. Typical immunization strategies involve delivery of attenuated pathogens or their products via intramuscular injections an approach which introduces a number of complications due to logistic limitations in vaccine transportation, distribution, administration and safe disposal. In contrast, epicutaneous immunization (EPI), involving immunogens delivered via surface application on the skin, offers an exciting alternative vaccination strategy. While there is much enthusiasm for this novel approach, relatively little is known about its efficacy at priming long-lived cell-mediated memory responses capable of protective immunity to pathogens. In this proposal, we will explore the use of epicutaneous immunization to prime CDS T cell responses capable of controlling various viral and bacterial pathogens in mice. In Aim 1, we will test the impact of various Toll-like receptors (TLR) on EPI, with a special emphasis on whether epicutaneous priming induces long lived memory T cells, capable of controlling pathogens. The ability to boost this response will also be tested here. In Aim 2, we focus on reports that the response to the pathogen Listeria monocytogenes is radically altered when mice are exposed to different TLRs, and when there is an imbalance of IL-12 versus Type-l Interferons. We will explore how this might limit the use of epicutaneous vaccination for this pathogen. In Aim 3, we study the effects of UV irradiation on EPI. UV irradiation, as might occur with mild sunburn, is known to suppress some cellular immune responses. We will determine what inhibitory effect UV has on epicutaneous vaccination approaches, and how this can be controlled.